Reverse transcription is a common feature of retrovirus replication. Viral replication requires a virally encoded reverse transcriptase to generate DNA copies of viral sequences by reverse transcription of the viral RNA genome. Reverse transcriptase, therefore, is a clinically relevant target for the chemotherapy of retroviral infections because the inhibition of virally encoded reverse transcriptase would interrupt viral replication.
An extremely promising and active area of research is in the discovery of non-nucleoside HIV reverse transcriptase inhibitors. Commonly assigned U.S. patent application Ser. No. 09/056,820(PCT Application WO98/45276) discloses novel quinazolinones of formula (I) as active non-nucleoside HIV reverse transcriptase inhibitors. ##STR1##
Due to the importance of this structural class, methods to synthesize the quinazolinone core which are amenable to industrial manufacture are needed.
Previous methods to prepare quinazolinones have employed dehydration of a quinazolinone, followed by 1,4 nucleophilic addition. Sternbach et al., Journal of Organic Chemistry, 1966, 31, 1007. International publication WO 93/04047 discloses the application of this methodology to the preparation of quinazolinone derivatives which are inhibitors of HIV reverse transcriptase (Scheme 1). ##STR2##
In this methodology, however, the 1,4 addition of R.sup.2 occurs without stereoselectivity. A manufacturing process which attempts to exploit this teaching would require tedious separation of the undesired enantiomer, making this approach unfeasible for reasons related to both cost and scale. Moreover, the dehydration protocol teaches thermal conditions, which may prove hazardous on an industrial scale.
The present invention finds utility in the asymmetric preparation of quinazolinone derivatives. By dehydrating a quinazolinone containing a chiral R.sup.8, the subsequent 1,4 nucleophilic addition is directed to afford the desired stereochemistry (Scheme 2). Removal of the directing group then affords the target compound. ##STR3##
The dehydration of the hemiaminal preferably occurs through the use of a dehydrating agent. This discovery allows for the safe preparation of electron deficient quinazolinones which are known to be resistant to dehydration. Additionally, convenient conditions for the preparation of the desired hemiaminal from an .alpha.-ketoaniline and a chiral isocyanate are disclosed. As a result, these important compounds can be prepared safely and efficiently.